Airway diseases are the most common of the lung disorders, however, treatment for these illnesses remains inadequate. Epidemiologic data indicates that a gender disparity exists in patients with airway diseases including bronchiectasis, asthma, and chronic obstructive lung disease, with women demonstrating worse severity and outcomes along with an increased prevalence in some circumstances. Few studies have addressed the biologic basis of this disparity, but sex hormones are a potentially important variable. A full understanding of the hormonal influences on the airways may lead to novel therapies to help treat these debilitating illnesses. In airway disease, the mucociliary apparatus, made up of cilia, mucous, and airway epithelial cell surface liquid, plays a critical role in protecting the lung from pathogens and is a target for hormone regulation. Indeed, our preliminary data indicates that female sex hormones alter mucociliary function. Accordingly, the goal of this proposal is to determine the impact of sex hormones, specifically progesterone, on mucociliary clearance, as a basis of explanation for the gender disparity in airways diseases. The central hypothesis is that women have more severe airway diseases than men due to progesterone-mediated alterations in airway epithelial mucociliary function. The long term goals of these studies are to understand the mechanisms leading to gender differences in airway diseases, improve current treatment, and develop novel therapies. To address these long term goals, we will apply a bench-to-bedside approach to this proposal by pursuing three specific aims at the in vitro, in vivo, and clinical levels. In Aim 1, we will characterize progesterone receptor expression, cell specificity, and receptor trafficking in primary human airway cells and in human lung tissues. In Aim 2, we will determine the impact of progesterone on mucociliary clearance by comparing cilia beat frequency of primary human airway epithelial cells in hormone stimulated conditions and by measuring airway clearance in hormone manipulated mice. We will also evaluate progesterone-dependent pathways that influence airway epithelial cell function to understand the mechanisms involved in sex hormone influences on mucociliary clearance. In Aim 3, using Cystic Fibrosis (CF) bronchiectasis as a model airway disease, we will utilize the national CF Foundation registry to retrospectively compare lung function and pulmonary exacerbations in men and women pre- and post-puberty and recruit CF bronchiectasis women locally to prospectively assess lung health during hormonal phases of the ovulatory cycle. Further understanding of these findings could lead to new therapeutic approaches involving inhaled hormone manipulation in bronchiectasis and other airway diseases. This work, in combination with a program of mentored research and a targeted educational program, will serve as the foundation for the PI's physician-scientist career.